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Endogenous basal nitric oxide production does not control myocardial oxygen consumption or function
J D Sadoff1, P M Scholz, H R Weiss
1Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick 08903-0019, USA.
Insights
Endogenous nitric oxide (NO) production in the heart does not appear to affect myocardial oxygen consumption or function. Inhibiting NO synthase with L-NAME and L-NMMA caused vasoconstriction but no changes in cardiac work or energy use.
Area of Science:
- Cardiovascular Physiology
- Biochemistry
Background:
- Previous studies demonstrated exogenous nitric oxide (NO) donors induce vasodilation and negative inotropy via guanylate cyclase activation and cyclic GMP increase.
- The role of endogenous myocardial NO production in regulating myocardial oxygen consumption and cardiac function in vivo remained unclear.
Purpose of the Study:
- To test the hypothesis that endogenous myocardial NO production limits myocardial oxygen consumption and function in vivo.
- To investigate the effects of NO synthase inhibition on coronary blood flow, myocardial oxygen consumption, cardiac work, and cyclic GMP levels.
Main Methods:
- Utilized NO synthase inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs.
- Administered inhibitors into the left anterior descending coronary artery (LAD), with the circumflex (CFX) artery serving as a control.
- Measured regional segment work, local myocardial O2 consumption, and myocardial cyclic GMP levels.
Main Results:
- L-NAME and L-NMMA induced local coronary vasoconstriction and increased O2 extraction.
- No significant changes were observed in local myocardial O2 consumption, segment force, percent shortening, or segment work.
- Myocardial cyclic GMP levels remained comparable between the LAD and control regions.
Conclusions:
- Blockade of endogenous NO production with L-NAME and L-NMMA effectively causes cardiac vasoconstriction in anesthetized dogs.
- The administered doses of NO synthase inhibitors did not alter local myocardial function, oxygen consumption, or cyclic GMP levels.
Abstract:
Previous studies from our laboratory have shown that an extrinsic nitric oxide (NO) donor (i.e., nitroprusside) caused vasodilatation and negative inotropy by activating guanylate cyclase and increasing myocardial cyclic GMP. We tested the hypothesis that endogenous myocardial NO production would limit myocardial oxygen consumption and function in vivo. We used the NO synthase inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) in nine open-chest anesthetized mongrel dogs. Either L-NAME (6 mg/kg) or L-NMMA (3 mg/kg) were infused into the left anterior descending coronary artery (LAD). The circumflex (CFX) coronary artery region served as a control. Regional segment work was calculated as the integrated product of local force (miniature transducer) and segment shortening (ultrasonic crystals). Local myocardial O2 consumption was determined using an ultrasonic LAD flow probe and local arterial-venous O2 content difference (oximetry). Cyclic GMP levels were obtained via a radioimmunoassay. Both L-NAME and L-NMMA caused a local decrease in coronary blood flow (LAD flow: 80 +/- 8 to 69 +/- 7 ml/min/100 g [means +/- SEM]) and increased O2 extraction (9.1 +/- 0.6 to 10.2 +/- 0.7 ml O2/100 ml). However, this led to no change in local O2 consumption. LAD segment force was not altered (12.1 +/- 0.7 to 11.6 +/- 0.9 g), nor was the percent shortening changed (10.8 +/- 1.8% to 10.0 +/- 1.4%) by L-NAME or L-NMMA, leading to no net change in segment work. Myocardial cyclic GMP levels were not different in a comparison between the LAD (1.7 +/- 0.4 pmoles/g) and control (1.7 +/- 0.2) regions with either L-NAME or L-NMMA. We conclude that blockade of endogenous NO production with L-NAME and L-NMMA is sufficient to cause vasoconstriction in the heart of anesthetized dogs. However, this dose did not lead to alteration in local myocardial function, O2 consumption, or cyclic GMP levels.